Hypoxia mediates a striking effect on cell cycle progression (Amellem and Pettersen 1991;Amellem et al. 1998) revealed that mammalian cells in general tend to accumulate in the G1 phase of the cell cycle during prolonged hypoxia. It has been reported that this accumulation results from three processes: [(a) retinoblastoma protein (pRb)- mediated cell cycle arrest in mid-G1; (b) activation of an oxygen-sensitive restriction point in late G1, close to the G1/S border; and (c) inhibition of DNA replication.]

Amellem O, Pettersen EO (1991) The role of protein accumulation on the kinetics of entry into S phase following extreme hypoxia. Anticancer Res 11:1083-1087

As mentioned above, exposure to hypoxia mediates a striking effect on cell cycle progression. Amellem et al. [43, 44] revealed that mammalian cells in general tend to accumulate in the G1 phase of the cell cycle during prolonged hypoxia. It has been reported that this accumulation results from three processes: (a) retinoblastoma protein (pRb)- mediated cell cycle arrest in mid-G1; (b) activation of an oxygen- sensitive restriction point in late G1, close to the G1/S border; and (c) inhibition of DNA replication.

From the final chapter of Iam's thesis ("Discussion"): Nothing has been marked as a citation, though the texts and the list of the references are identical. The source is mentioned in the legend to the accompanying figure 26.

[It has been reported that this accumulation results from three processes:] (a) retinoblastoma protein (pRb)- mediated cell cycle arrest in mid-G1; (b) activation of an oxygen-sensitive restriction point in late G1, close to the G1/S border; and (c) inhibition of DNA replication. It was furthermore demonstrated that cells in G2, mitosis, or early G1 by the onset of hypoxia progress to the pRb mediated checkpoint in mid-G1 during continuation of hypoxic exposure. In contrast, pRb-incompetent cells or cells that have already passed this mid-G1 checkpoint continue cell cycle progression until they are blocked in the oxygen-sensitive restriction point close to the G1/S boundary. Moreover, cells in the S phase, when rendered hypoxic, are immediately arrested and are inactivated after only a few hours of oxygen deprivation. In general, cells residing in the S phase at the time of hypoxic conditions are much more sensitive to the lethal effects of hypoxia than cells in any other stage of the cell cycle. Consequently, following prolonged severe hypoxia, most clonogenic cells are arrested in one of the two restriction points in G1 (Amellem and Pettersen 1991; Amellem et al. 1998; Koritzinsky et al. 2001). The reason why low oxygen tension is associated with radioresistance relies on the fact that cell killing by ionizing radiation is caused by damage to the DNA. Either direct ionization or reaction of the radiation with hydroxyl radicals produced by radiolysis of nearby water molecules results in the origin of DNA radicals.

Amellem O, Pettersen EO (1991) The role of protein accumulation on the kinetics of entry into S phase following extreme hypoxia. Anticancer Res 11:1083-1087

It has been reported that this accumulation results from three processes: (a) retinoblastoma protein (pRb)- mediated cell cycle arrest in mid-G1; (b) activation of an oxygen- sensitive restriction point in late G1, close to the G1/S border; and (c) inhibition of DNA replication.

It was furthermore demonstrated that cells in G2, mitosis, or early G1 by the onset of hypoxia progress to the pRb-mediated checkpoint in mid-G1 during continuation of hypoxic exposure. In contrast, pRb-incompetent cells or cells that have already passed this mid-G1 checkpoint continue cell cycle progression until they are blocked in the oxygen-sensitive restriction point close to the G1/S boundary. Moreover, cells in the S phase, when rendered hypoxic, are immediately arrested and are inactivated after only a few hours of oxygen deprivation. In general, cells residing in the S phase at the time of hypoxic conditions are much more sensitive to the lethal effects of hypoxia than cells in any other stage of the cell cycle. Consequently, following prolonged severe hypoxia, most clonogenic cells are arrested in one of the two restriction points in G1 [31, 43, 44].

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The reason why low oxygen tension is associated with radioresistance relies on the fact that cell killing by ionizing radiation is caused by damage to the DNA. Either direct ionization or reaction of the radiation with hydroxyl radicals produced by radiolysis of nearby water molecules results in the origin of DNA radicals.